Tracey Regan

Since its approval in 1998 to treat metastatic disease, trastuzumab has dramatically expanded life expectancy and improved quality of life for women diagnosed with HER2-positive breast cancer. It remains the standard-of-care, first-line treatment for metastatic breast cancer. In less than a decade, the FDA has added three new drugs to the arsenal to treat advanced HER2-positive disease, while a growing number of clinical studies are evaluating dual-agent approaches to therapy through a variety of drug combinations.

At the MBCC mini-symposium Thursday, Kimberly L. Blackwell, MD, the director of the Breast Cancer Program at Duke Cancer Institute, discussed current treatment options in a presentation entitled &ldquo;Targeting HER2 in Metastatic Breast Cancer in 2014.&rdquo; She put emerging treatment trends into context during an interview in advance of her talk.

How have treatment options and prognoses changed over the past decade for women diagnosed with HER2-positive breast cancer?

We can no longer speak of diagnosing breast cancer in broad terms, but rather of different subtypes of breast cancer and cancer stage. Prognoses, based on a specific cancer&rsquo;s biology, are very different. But we can say that the prospects for women diagnosed with HER2-positive breast cancer have improved. With certain subtypes, discovered in the early stages of the disease, we can start talking about a cure. This marks a paradigm change; we could not have said this 10 years ago. There are now people with HER2-positive disease who have no recurrence if they are treated earlystage with trastuzumab. The prognosis for these women is pretty tremendous, and it has allowed us to save years and years of life for them.

How have prospects changed for women with HER2- positive metastatic disease?

There are a lot of options for these women if their cancer remains HER2-dependent. We now treat metastatic breast cancer as we would a chronic disease, such as diabetes or heart disease, with targeted therapies and combinations of therapies.

A serious challenge we face with some of these women, however, is brain metastases. This is a tragic situation, especially for women who have lived a high-quality life for several years and then develop metastases. It is a difficult cancer to treat, and these patients may also suffer the long-term effects of stroke. We must recognize that we aren&rsquo;t able to adequately treat progressive brain metastasis.

Where are the post-trastuzumab drugs proving most effective, and in what settings?

The approval of T-DM1, an antibody-drug conjugate, is changing the way we care for metastatic breast cancer and solid tumors in general. Treatment that doesn&rsquo;t hurt the immune system is a major breakthrough that will improve patient care. Lapatinib is not super effective therapeutically. We see that lapatinib and trastuzumab are more effective together than lapatinib alone. But there may be new life for this drug. The data we have now do not look at combinations with T-DM1 or the effect of layering trastuzumab with lapatinib or pertuzumab.

What role are dual-agent therapies playing in the treatment of metastatic disease?

We&rsquo;re doubling down on HER2-positive cancer. There will be few studies from now on that evaluate trastuzumab alone; in metastatic breast cancer, dual agents are here. The dilemma facing clinicians over the next 5 years is going to be sequencing.

How do the newer drugs improve upon the performance of trastuzumab?

There is a limited ability to improve upon trastuzumab&rsquo;s performance with these newer drugs. There are studies whose results we&rsquo;re anxiously awaiting, but it&rsquo;s really unclear how useful they will be. With healthcare reform and the cost to society of developing and prescribing new drugs, we need to look very carefully at the value of small incremental gains and to ask some very hard questions as a society: Is it worthwhile to add new medications? How many people need these new expensive therapies?

Are there drugs on the horizon that may improve treatment for HER2-positive disease?

Everolimus [approved in HER2-negative settings] may prove valuable. While it showed only a small improvement in progression-free survival in BOLERO-3 (1.2 months), I don&rsquo;t dismiss it. I think its capacity to cross the blood-brain barrier is important and it may prove useful in addressing brain metastases. I think we will also see neratinib come to the table. We saw in the I-SPY 2 study of neratinib in the neoadjuvant setting that it met its primary endpoint. I think that studies of PI3-kinase inhibitors are also going to yield some interesting results.

This is the therapeutic area I&rsquo;m most excited about now. If trastuzumab can make such a difference and it&rsquo;s a monoclonal antibody, we can only imagine what a polyclonal response would be like. A proven vaccine in the HER2-positive sphere would have a huge impact. The obstacle to a vaccine is that it&rsquo;s hard to develop. We would also need to figure out which patients are capable of mounting an immune response, which aren&rsquo;t, and then determine how to screen for that.

Which clinical studies stand to have the largest impact on the direction of treatment?

In metastatic disease, we are waiting for full results from MARIANNE, which for the first time evaluates whether T-DM1 alone or combined with pertuzumab is better than trastuzumab and a taxane. This could [establish T-DM1] as a first-line therapy in metastatic disease, and so MARIANNE is a game-changing study. The APHINITY trial, [which compares trastuzumab plus chemotherapy with and without pertuzumab as adjuvant therapy for primary breast cancer] will also be important. A question for clinicians going forward will be whether to choose pertuzumab or lapatinib in the adjuvant setting. This will be a dilemma, and the answer will be driven by patient-reported outcomes.

How effectively are we diagnosing and treating molecular subtypes of breast cancer?

We now have the capability to look at 50 genes linked with breast cancer. What&rsquo;s missing is not the ability to accurately characterize cancers through diagnostic testing, but the infrastructure that allows practicing doctors to do this and then select appropriate treatments for their patients based on it. We need to have a transparent dialogue about what&rsquo;s holding up getting this capability to the clinic, and then to forge a commercial/academic partnership to get it done. It will be important to develop an assay that we can all use regularly, and I believe there should be financial incentives to deliver this assay. I use the Oncotype DX test because I feel it helps me take better care of my patients.

Articles

Since its approval in 1998 to treat metastatic disease, trastuzumab has dramatically expanded life expectancy and improved quality of life for women diagnosed with HER2-positive breast cancer.

Q & A With Kimberly L. Blackwell: The Treatment of HER2 Metastatic Breast Cancer

interviewed Cy Stein, MD, PhD, Arthur & Rosalie Kaplan Chair in Medical Oncology and deputy director of Clinical Research at City of Hope National Medical Center, and a member of the NCCN guideline panel for prostate cancer.

: Is there optimal sequencing for androgen-deprivation therapy (ADT)?

There is probably no such thing as optimal sequencing from what we currently know about treatment; we have no proof of what it would be as yet. In fact, one clinician&rsquo;s course of treatment may be as good as another&rsquo;s. What is there still to learn about this? In short, everything. My thought, however, is that even when we know more, we will discover that there is still no fixed sequence. Treatment is likely to continue to be very individualized, because patients--and the disease itself--are heterogeneous. A lot of art will remain in the care of these patients. Some disease is indolent and some is very aggressive. Some of our older patients are able to tolerate very little and have well defined views about quality of life for their remaining years. Younger men often feel differently and are eager to try new approaches.

What are some of the drug sequences physicians are currently using?

For metastatic disease, the antiandrogen bicalutamide can be prescribed. Some doctors in academic centers will then give the immunotherapy sipuleucel-T, but that&rsquo;s more difficult for community oncologists for reasons of cost, insurance coverage, and administration. Many doctors now prescribe the CYP17 inhibitor abiraterone, while others start with androgen receptor inhibitor enzalutamide, even though it doesn&rsquo;t have FDA approval yet in the pre-chemo space. Despite this, some insurers will still say yes to it.

There is arbitrariness to some of these decisions. Do we employ these new agents pre-chemotherapy or post-chemotherapy? Most of us believe, for example, that if an agent is active post-chemo, then it&rsquo;s active pre-chemo as well. Abiraterone is a little tougher to give than enzalutamide. If the patient is diabetic, it can be a problem because it must be given with the steroid prednisone, and abiraterone also can cause electrolyte imbalances and exacerbate liver problems. While enzalutamide is less toxic, it is not without issues, including altered mental status and seizures in rare cases, and some fatigue as well.

So it&rsquo;s something of a toss-up with these two new agents. Studies have shown that enzalutamide is not that effective after abiraterone, and vice versa. There are still other options. After ADT, doctors will often recommend chemotherapy. If docetaxel fails, clinicians can go with abiraterone or enzalutamide, or radium-223, or the chemotherapy cabazitaxel. The variability between individuals is so huge, there&rsquo;s no set plan.

Do any drug combinations that include ADT look promising?

Many of these combinations are still in trials, which include several with abiraterone and enzalutamide. It&rsquo;s too early to tell what is effective. There is a trial of LHRH agonist Lupron (leuprolide acetate) plus bicalutamide versus Lupron plus enzalutamide. There is also enzalutamide combined with abiraterone. While we sometimes think we know what the answers to these trials will be, we have learned to discount that kind of thinking, as we&rsquo;ve been burned before. We need solid evidence.

What guides decision-making in prescribing ADT?

That is a very difficult question. There are no hard-and-fast rules when you start this therapy, although there are some general guidelines. If the disease is progressing rapidly, the indications are to change therapy. But this doesn&rsquo;t happen in many patients. Often, we don&rsquo;t see symptoms, but rather just an increase in PSA. But what does a small increase in PSA mean? Do we treat a number?

The answer is no. In fact, it&rsquo;s not the number that matters so much as the rate of increase. If PSA doubles in 5 or 6 months, then we might try enzalutamide or abiraterone. If it doubles in a year or more, we may choose to watch and wait. In terms of prescribing the newer agents, few people have bad reactions, except for patients with health issues such as poor liver function who are taking abiraterone or a seizure disorder if enzalutamide is chosen. The androgen receptor is a bad actor until very late in the disease, so everyone is potentially a candidate for these therapies. With long exposure to abiraterone, enzalutamide will likely be less effective. But you can&rsquo;t necessarily deny it to a patient based on that, because it may in fact work. So often with prostate cancer, we can&rsquo;t predict.

What strides are we making in identifying biomarkers that will help predict the efficacy of treatment?

This, too, is difficult to say. There is PSA, but we know that it is not necessarily predictive. A high Gleason score or a high PSA to begin with may be signs of aggressive or advanced disease. But even these high numbers must be considered individually in each patient. In some cases, even a high PSA may not mean that much. For example, a PSA of 20 in one person may be like 1000 in another. There are all kinds of studies out there trying to validate additional biomarkers, but again, the problem is heterogeneity. Too many times the results wash out, despite initial promise.

There is ARN-509, which acts like bicalutamide on steroids. It seems interesting, but those trials are not advanced enough to say much. We have no sense yet, for example, of overall survival, which is the gold standard. There are some other drugs that are closely related to abiraterone, such as galeterone, a CYP17 inhibitor and androgen receptor antagonist. There is also the CYP17 inhibitor TAK-700, although it recently missed its primary endpoint of increasing overall survival. However, it&rsquo;s getting to be a crowded space for those drugs, so it&rsquo;s easy to miss an endpoint. Clinicians will be looking at it in earlier-stage cancer, but it&rsquo;s too early to tell.

How are these new agents changing clinical practice?

Targeted Oncology interviewed Cy Stein, MD, PhD, Arthur & Rosalie Kaplan Chair in Medical Oncology and deputy director of Clinical Research at City of Hope National Medical Center.

Expert Perspectives: Androgen-Deprivation Therapy in Prostate Cancer

The efficacy and safety of adding the experimental agent brentuximab vedotin (Adcetris) to standard chemotherapy to treat patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) is being evaluated in a randomized, open-label phase II trial.

Brentuximab vedotin is an antibody-drug conjugate (ADC) that binds with CD30, a protein expressed on the surface of lymphoma cells, to deliver a powerful cytotoxin. The study will combine brentuximab with R-CHOP, the standard frontline therapy for DLBCL, the most common form of non- Hodgkin lymphoma with more than 20,000 new cases per year.

The drug is among a number of novel therapies now being tested in conjunction with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) to improve outcomes for patients with high-risk, aggressive lymphoma, a subgroup for which current therapies help only half of patients.

&ldquo;While patients with the most advanced disease have a 50/50 chance of survival, we hope to do better. There are now several trials like this one that are attempting to take the next step,&rdquo; said Nancy Bartlett, MD, the Koman Chair in Medical Oncology at Washington University School of Medicine in St. Louis, Missouri, and the principal investigator for the trial. &ldquo;The addition of R to CHOP about 10 years ago was the first major improvement in the treatment of DLBCL in nearly 30 years. The hope is that combining R-CHOP with other targeted agents with unique mechanisms of action may increase survival rates even further.&rdquo;

&ldquo;There are no biomarkers or screening tests for lymphoma, in contrast to tests such as PSA in prostate cancer, and mammogram and colonoscopy in breast and colon cancers,&rdquo; Bartlett said. &ldquo;Patients have symptoms such as swollen lymph nodes, abdominal pain and bloating, and they move quickly on to biopsies. This is an aggressive disease that you want to diagnose and treat as quickly as possible.&rdquo;

To be eligible for the study, participants must be newly diagnosed and at high riskdefined as scoring a 3 or higher on the IPI Index, a prognostic tool consisting of five factors, including age over 60 years, poor performance status, extra nodal sites, stage 3 or 4 disease, and elevated levels of lactase dehydrogenase (LDH).

&ldquo;How well DLBCL patients do depends on disease stage and other prognostic factors determined by the IPI Index. For young, early-stage patients with good lab reports, the cure rate is 90%. But if you have three, four, or five factors from the IPI Index, your chance of a cure with R CHOP is in the 55% to 60% range,&rdquo; Bartlett said, adding that high-risk patients were selected for the trial as they are &ldquo;more likely to benefit from new approaches.&rdquo;

The trial will divide 50 patients between two arms. Half will receive brentuximab vedotin 1.8 mg/kg plus R-CHOP every 3 weeks for up to six cycles. The other half will receive 1.2 mg/kg brentuximab vedotin plus R-CHOP, on the same schedule.

&ldquo;We&rsquo;re looking for effectiveness, but also for side effects. One concern is that we&rsquo;re mixing drugs that have never been combined before,&rdquo; Bartlett said. &ldquo;We&rsquo;re combining two tubulin inhibitors brentuximab vedotin and vincristine&mdash;which can both cause peripheral neuropathy. So we&rsquo;ll see what happens if we use the two together. Will we see more neuropathy? Will there be less neuropathy at the lower dose of brentuximab vedotin with the same level of tumor activity? We need to tease out both of those questions.&rdquo;

TABLE. A Phase 2 Study of Brentuximab Vedotin in Combination with Standard of Care Treatment (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone [R-CHOP]) as Front-line Therapy in Patients with Diffuse Large B-Cell Lymphoma (DLBCL)

CLINICALTRIALS.GOV IDENTIFIER: NCT01844505

Complete remission rate over a time frame of up to 6 months; incidence of adverse events; incidence of laboratory abnormalities

Objective response rate over a time frame of up to 6 months; progression-free survival over a time frame of up to approximately 4 years; overall survival over a time frame of up to approximately 4 years

Treatment-na&iuml;ve patients with systemic de novo or transformed diffuse large B cell lymphoma or follicular non-Hodgkin lymphoma grade 3b

International Prognostic Index score &ge; 3

Stage IAX (bulk defined as single lymph node mass > 10 cm in diameter), IB-IV disease

Eastern Cooperative Oncology Group performance status &le; 2

No previous treatment for indolent lymphoma

No previous other primary malignancy that has not been in remission for 3 years

Brentuximab vedotin 1.2 mg/kg administered intravenously every 3 weeks for up to 6 cycles plus R-CHOP (rituximab 375 mg/m

every 3 weeks by IV infusion for up to 6 cycles; vincristine 1.4 mg/m

every 3 weeks by IV infusion for up to 6 cycles (dose capped at 2 mg total); cyclophosphamide 750 mg/m

every 3 weeks by IV infusion for up to 6 cycles; prednisone 100 mg on days 1-5 of each 3-week cycle, orally for up to 6 cycles; doxorubicin 50 mg/m

every 3 weeks by IV infusion for up to 6 cycles

Brentuximab vedotin 1.8 mg/kg administered intravenously every 3 weeks for up to 6 cycles plus R-CHOP (rituximab 375 mg/m

The most common treatment-emergent adverse events observed in a previous phase II trial for patients with relapsed B-cell lymphoma who received single-agent brentuximab vedotin were neutropenia, fatigue, nausea, and diarrhea. The most common grade 3 or 4 adverse events in that trial were neutropenia (25% grade 3; 11% grade 4) and anemia (9% grade 3).

The primary outcome measures in the trial are complete remission rate up to six months, as well as the incidence of adverse events and laboratory abnormalities. Secondary endpoints include objective response rate (ORR) up to six months, progression- free survival for up to approximately four years, and overall survival over four years.

Bartlett said she was encouraged by results from an earlier phase II trial for relapsed B-cell lymphoma that included 44 patients who received single- agent brentuximab vedotin, including 25 with DLBCL. Among patients with DLBCL the ORR was 44% (11 of 25), including 20% complete remissions and 24% partial remissions.

The most common treatment-emergent adverse events were neutropenia (43%), fatigue (36%), nausea (34%), and diarrhea (32%). The most common Grade 3 or 4 adverse events were neutropenia (25% Grade 3; 11% Grade 4) and anemia (9% Grade 3).

&ldquo;Of the two dozen DLBCL patients enrolled in that trial, between 40% and 45% had at least a partial remission, including, interestingly, those with very low levels of CD30 expression,&rdquo; she said. &ldquo;It was encouraging to see the drug&rsquo;s activity in those patients. The drug was well tolerated, too, with manageable side effects.&rdquo;

Of the current study, Bartlett noted, &ldquo;This is a small trial and we won&rsquo;t draw huge conclusions from it as we would if we were comparing the drug to R-CHOP alone. It will give us preliminary information hypothesis-generating information. We will be looking at PET scans, and if the results look promising, we&rsquo;ll decide if it&rsquo;s worth pursuing this combination in a larger group of patients. We will want to know how much more peripheral neuropathy we see and how quickly it resolves.&rdquo;

Enrollees are identified through customary testing for DLBCLstandard lab tests, LDH tests, organ CT and PET scans, and bone marrow biopsies. They are being offered a follow-up biopsy 24 to 72 hours after the first dose to assess the drug&rsquo;s immediate impact.

In a departure from the earlier trial, patients enrolling in the current study are not required to be CD30-positive.

&ldquo;The hypothesis is that there may be CD30 expression at lower levels that we&rsquo;re not detecting,&rdquo; Bartlett said, noting that the drug was developed to combat diseases with known high levels of CD30, including Hodgkin lymphoma and ALCL, in which it is diagnostic. &ldquo;Following that, the idea was to see if other cancers have CD30, and in DLBCL, 10% to 30% of patients express it although not at high levels on malignant cells. But in the earlier trial, we saw responses even in patients with no detectable levels, raising questions about whether it is somewhere else in the cell, other than on the surface, that tests are not picking up.&rdquo;

Little is known to date about CD30&rsquo;s role as a cancer driver. Rather, the protein was selected as a target for ADC development for the access it provides to cancer cells and because it is highly expressed on malignant cells but rarely on normal cells.

&ldquo;[Brentuximab vedotin] is not a drug that targets a specific cellular pathway. Instead, it employs a surface antigen target approach. The thinking behind ADCs is to define a cancer population by cell surface antigen expression and concentrate cytotoxic agents where it matters, while sparing normal tissue,&rdquo; said Eric Sievers, MD, senior vice president of Clinical Development for the drug&rsquo;s maker, Seattle Genetics.

&ldquo;In this case, CD30 is the targetthe handle by which we latch onto the cancer cell with the antibody and then enter it like a Trojan horse to deliver the cytotoxic agent, auristatin, a synthetic compound modeled on dolastatin, a toxic chemical produced by the Indian Ocean sea hare.&rdquo;

The FDA approved brentuximab vedotin two years ago to treat relapsed Hodgkin lymphoma (HL) and systemic anaplastic large cell lymphoma (sALCL) under its Accelerated Review program, which allows the agency to approve a drug to treat a serious disease based on clinical data showing the drug has an effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit to patients. It was the first new FDA-approved treatment for HL since 1977 and the first specifically indicated to treat ALCL.

The approval was based on the results from two single-arm studies in which the drug was used alone to treat patients with HL and ALCL. The primary endpoints of both trials were ORRthe percentage of patients who experienced complete or partial cancer shrinkage or disappearance after treatment. In the HL trial, 73% of patients achieved either a complete or partial response to the treatment, and on average responded to the therapy for 6.7 months. In the ALCL trial, 86% of patients experienced either a complete or partial response and responded on average for 13.2 months.

There are now approximately three dozen clinical trials evaluating the drug that are either planned or are actively recruiting patients. In the company&rsquo;s large, global phase III clinical trials, ECHELON-1 and ECHELON-2, the drug is being tested as a frontline treatment in Hodgkin lymphoma and mature T-cell lymphoma (MTCL), including in patients with sALCL and other types of peripheral T-cell lymphoma.

&ldquo;From what we know, CD30 is mostly limited to lymphomas, with some interesting exceptions, including embryonal germ cell tumors, a form of testicular cancer, and possibly leukemias. That&rsquo;s where our research is taking us,&rdquo; Sievers said.

Brentuximab Vedotin as Frontline Therapy in Diffuse Large B-Cell Lymphoma

The efficacy of combining two immunotherapy agents to treat advanced melanoma will be assessed in a randomized, double-blind phase III study that will measure the combination&rsquo;s ability to prolong survival in patients with newly diagnosed metastatic disease.

The two agents, nivolumab and ipilimumab, are immune checkpoint inhibitors, monoclonal antibodies that target distinct pathways that tumor cells use to prevent the immune system from mobilizing against them. Although the drugs operate independently to stimulate the body&rsquo;s defenses, results from an earlier trial suggest that their antitumor action is complementary, making them more effective when deployed together than as single agents. The current trial, CheckMate 067, is designed to test that hypothesis directly.

Nivolumab, an investigational compound, binds with the programmed death-1 (PD-1) receptor on activated T-cells, preventing them from interacting with tumor proteins that weaken the ability of T-cells to fight disease. Ipilimumab, approved by the FDA in 2011 to treat melanoma patients with advanced disease, adheres to another T-cell receptor, cytotoxic T-lymphocyte antigen-4 (CTLA-4), blocking it from binding with tumor proteins. PD-1 contributes to T-cell exhaustion in peripheral tissues, and CTLA-4 inhibits at earlier points in T-cell activation.

&ldquo;The goal is to induce a more robust immune response. The best case response is durable regression in a large number of patients,&rdquo; said Jedd D. Wolchok, MD, PhD, associate director of the Ludwig Center for Cancer Immunotherapy at Memorial Sloan-Kettering Cancer Center in New York City, and the principal investigator for the trial.

In the phase III trial now under way, more than 900 patients with newly diagnosed metastatic disease and no prior systemic therapy will be divided among three arms. One group will take nivolumab plus ipilimumab, a second cohort will be given nivolumab alone, and a third group will receive ipilimumab alone. To maintain the blinded nature of the trial, all patients will come in 2 out of every 3 weeks to receive injections, Wolchok said.

The dosing combination of nivolumab at 1 mg per kilogram of body weight and ipilimumab at 3 mg per kilogram, established as safe and effective in a phase I trial,

has been carried over to the current study. Patients in the phase III trial will also receive nivolumab maintenance therapy after the combination therapy, receiving nivolumab alone every 2 weeks after 12 weeks for up to 2 years. &ldquo;We combine the two agents upfront for activity and then proceed to maintenance,&rdquo; Wolchok said.

The primary endpoint of the CheckMate 067 trial is overall survival (OS). Secondary outcome measures include progression-free survival (PFS) and objective response rate (ORR).

Results from the earlier dose-escalation trial were encouraging, Wolchok said. Although not formally compared in that study, concurrent treatment with nivolumab and ipilimumab was associated with ORRs that exceeded the previously reported results with either nivolumab or ipilimumab alone.

TABLE. Phase III Study of Nivolumab or Nivolumab Plus Ipilimumab Versus Ipilimumab Alone in Previously Untreated Advanced Melanoma (CheckMate 067)

CLINICALTRIALS.GOV IDENTIFIER: NCT01774721

OS, with data collected continuously while subjects are on study medication and every 3 months via in-person or phone contact after discontinuation of study medication

PFS, with data collected on day 1 and week 12 and then every 6 weeks up to week 49, and then every 12 weeks; ORR, with data collected on day 1 and week 12 and every 6 weeks up to week 49, and then every 12 weeks until disease progression is documented; differences in OS, PFS, and ORR between the two experimental arms (time frame: OS: approximately up to 44.1 months); PFS and ORR: baseline (day 1), week 12, every 6 weeks thereafter up to week 49, and then every 12 weeks until disease progression is documented--approximately around 5 years; OS based on PD-L1 expression; mean changes from baseline in EORTC-QLQ-C30

Histologically confirmed stage III (unresectable) or stage IV melanoma

Measurable disease determined by computed tomography (CT) or magnetic resonance imaging (MRI)

Tumor tissue from an unresectable or metastatic site of disease for biomarker analyses

Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1

No prior treatment with an anti-programmed death receptor-1 (PD-1), anti-programmed death-1 ligand-1 (PD-L1), anti-PD-L2, or anti-cytotoxic T lymphocyte associated antigen-4 (anti-CTLA-4) antibody

No active brain metastases or leptomeningeal metastases

No active, known, or suspected autoimmune disease

No conditions requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of treatment

Nivolumab 3 mg/kg solution intravenously every 2 weeks plus placebo matching with ipilimumab 0 mg/kg solution intravenously on weeks 1 and 4 and placebo matching with nivolumab on week 4 for cycles 1 and 2, until documented disease progression, discontinuation due to toxicity, withdrawal of consent, or the end of the study

Nivolumab 1 mg/kg solution intravenously combined with ipilimumab 3 mg/kg solution intravenously every 3 weeks for 4 doses, followed by nivolumab 3 mg/kg solution intravenously every 2 weeks plus placebo matching with nivolumab on weeks 3 and 5 for cycles 1 and 2, until documented disease progression, discontinuation due to toxicity, withdrawal of consent, or the study ends

Ipilimumab 3 mg/kg solution intravenously every 3 weeks for a total of 4 doses plus placebo matching with nivolumab 0 mg/kg solution intravenously on weeks 3 and 5 for cycles 1 and 2, until documented disease progression, discontinuation due to toxicity, withdrawal of consent, or the study ends

Principal adverse events observed in the phase I study of nivolumab plus ipilimumab were fatigue, rash, itching, and diarrhea, and asymptomatic elevation of liver and pancreatic enzymes.

EORTC-QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30.

In the phase I study, patients in one multicohort arm took the drugs concurrently, receiving intravenous doses of nivolumab and ipilimumab every 3 weeks for four doses, followed by nivolumab alone every 3 weeks for four doses (concurrent regimen). The combined treatment was subsequently administered every 12 weeks for up to eight doses. A second arm followed a sequenced regimen in which patients previously treated with ipilimumab received nivolumab every 2 weeks for up to 48 doses.

Patients in the concurrent arm who received the maximum dosages deemed acceptable (nivolumab 1 mg/kg and ipilimumab 3 mg/kg) had the greatest response and had tumor reductions that were swift, substantial, and durable.

&ldquo;More than half of those patients exhibited tumor burden regression of greater than 80% by their first set of radiological scans at 12 weeks. This represents a speed and depth of response we hadn&rsquo;t seen yet with immunotherapy drugs,&rdquo; said Wolchok.

Responses were ongoing in about 90% of patients who responded to the combination therapy, with the duration ranging from 6.1 to 72.1 weeks at the time of data analysis in February 2013, according to published results. Median OS had not been reached after approximately 13 months of follow-up in the concurrent arm. The estimated 1-year survival rate across all concurrent cohorts with various dosing levels was 82% (95% CI, 69.0- 94.4).

Grade 3 or 4 adverse events (AEs) related to therapy occurred in 53% of patients in the concurrent- regimen group. AEs were similar to previous experience with monotherapy and were generally reversible. Treatment-related AEs in this arm included rash (55%), pruritus (47%), fatigue (38%), and diarrhea (34%). The most common grade 3/4 treatment-related AEs were elevations in lipase (13%), aspartate aminotransferase (13%), and alanine aminotransferase (11%). In the sequencedregimen arm, treatment-related AEs occurred in 73% of patients; the most common were pruritus (18%) and lipase elevation (12%). The most common grade 3/4 AE in this group was lipase elevation (6%).

In addition to the phase III CheckMate 067, the phase II CheckMate 064 trial is also recruiting participants. The trial will randomize patients with advanced or metastatic melanoma to a regimen of nivolumab sequentially with ipilimumab, and the primary endpoint is the incidence of treatmentrelated grade 3-5 AEs during the induction period (ClinicalTrials.gov Identifer NCT01783938).

Wolchok noted that prospects for patients with melanoma have improved measurably since he began practicing in 2000. He pointed to FDA approvals in 2011 for ipilimumab and vemurafenib, and to a number of new drugs in late-stage development. &ldquo;We now have conventional tools and new agents in development, and we are accruing a body of knowledge about which pathways drive this cancer,&rdquo; he said. &ldquo;The challenge is that it&rsquo;s a heterogeneous disease. Some people progress after a long time, while the process is much more rapid in others. In some cases, we&rsquo;re not sure which mutations are driving the cancer; we&rsquo;re learning in real time which take over when the disease becomes refractory.&rdquo;

Wolchok sees immunotherapy as a promising direction for cancer treatment. &ldquo;With immunotherapy we&rsquo;re treating the patient, not the cancer. It&rsquo;s a different mindset,&rdquo; he said. &ldquo;Responses with immunotherapy tend to be durable, keeping disease under control for longer periods of time.&rdquo;

Ipilimumab and nivolumab are immune system modulators; both were developed by Bristol-Myers Squibb. &ldquo;The immune system must defend the body, but not become overactivated so that it attacks itself. It has balances and checkpoints that we can press. PD-1 and CTLA-4 are checkpoints in that on/off system,&rdquo; said Fouad Namouni, MD, global development lead for nivolumab. &ldquo;With nivolumab and ipilimumab, we are trying to prevent the T-cell receptor ligands from access to that on/off button so that the immune system, turned off by cancer, can work again.&rdquo;

Research in the area began with investigations of the CTLA-4 pathway and the mechanisms that cancer uses to stimulate the pathway, causing the T-lymphocytes to become exhausted and ineffective against the tumor, he said. Ipilimumab, which was designed to block that action, demonstrated survival benefits in two phase III studies in patients with advanced disease.

&ldquo;This showed us for the first time that an immune system modulating agent could work,&rdquo; Namouni said. The results prompted further research of the PD-1 pathway, another major brake on the T-cell, and the ligand PD-L1, which is expressed by tumors to transform the T-cell from active to exhausted.

Investigators say there is still much to learn from the phase III study. Wolchok noted that it was not clear from the earlier study, for example, why some patients responded and others didn&rsquo;t, and research on potential biomarkers is ongoing.

&ldquo;We looked at tumors with a high level of the ligand PD-L1 expressed on the tumor cells to see if that played a major role,&rdquo; said Namouni. &ldquo;We wondered whether tumors with high levels would be most likely to respond. The answer appears to be not necessarily.&rdquo;

Of note, biomarkers relevant to each of the monotherapies (PD-L1 expression by tumor for nivolumab and absolute lymphocyte count for ipilimumab) may not be relevant for combination therapy.

Bristol-Myers Squibb is also exploring the use of immunotherapy in other tumor types. Based on data from a series of phase I trials, the company has accelerated its development program for nivolumab and now has seven potential registration trials in non-small cell lung cancer (NSCLC), advanced renal cell carcinoma, and advanced melanoma, including one in combination with ipilimumab. Phase I trials also are evaluating nivolumab in advanced hepatocellular carcinoma and hematologic malignancies. The company has begun exploratory work to better define what other tumor types may respond to nivolumab. Earlier this year, the FDA granted nivolumab Fast Track status for melanoma, lung cancer, and kidney cancer. Ipilimumab is being evaluated in phase III trials in NSCLC, smallcell lung cancer, and castration-resistant prostate cancer, and as adjuvant therapy in melanoma.

Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma.

Bristol-Myers Squibb. Bristol-Myers Squibb Announces Phase 1 Results from First Trial Combining Immune Checkpoint Inhibitors, Investigational Agent Nivolumab and Yervoy&reg; (ipilimumab), in Patients with Advanced Melanoma. June 2, 2013. Available at: http://news.bms.com/press-release/rd-news/bristol-myerssquibb- announces-phase-1-results-first-trial-combining-immune-ch. Accessed July 30, 2013.

The efficacy of combining two immunotherapy agents will be assessed in a randomized, double-blind phase III study.

CheckMate 067: Phase III Study of Nivolumab in Melanoma

The second-generation tyrosine kinase inhibitor (TKI) dacomitinib, designed to treat non-small-cell lung cancer (NSCLC), is being evaluated in an international phase III clinical trial that will measure the drug&rsquo;s effectiveness as a first-line treatment in a genetic subset of patients with locally advanced or metastatic disease.

Dacomitinib blocks three of the four human epidermal growth factor receptor (HER) signaling pathways, which are implicated in cancer growth, survival, and metastasis. In NSCLC, at least one member of the HER family of receptors is expressed in 90% of solid tumors, with 60% of those tumors containing abnormalities in a HER family member that contribute to tumor development.

In the phase III ARCHER 1050 trial now under way, dacominitib is being tested against gefitinib, a first-generation TKI, in patients with EGFR (HER1)-activating mutations, which affect 20% to 30% of Asians with NSCLC and up to 15% of Caucasians.

&ldquo;These are patients with advanced-stage adenocarcinoma with known

mutations. Obviously this is a potentially fatal disease if untreated,&rdquo; said Tony Mok, MD, professor of Clinical Oncology at the Chinese University of Hong Kong and principal investigator for the trial. &ldquo;The standard therapy is a first-generation EGFR TKI such as gefitinib or erlotinib. Tumor response rate is high and efficacy is good. However, resistance usually occurs within a year.&rdquo;

In nearly half of all cases, acquired resistance is caused by a secondary

binding pocket mutation. The drug, developed by Pfizer, Inc., is designed to overcome or delay the impact of that mutation, said Joseph O&rsquo;Connell, a senior director for Pfizer and the clinical lead for dacomitinib, who noted that the mutation alters the binding pocket&rsquo;s conformation &ldquo;and favors ATP (adenosine triphosphate) signaling, preventing the drugs from working.&rdquo;

&ldquo;Resistance in the other half of cases involves activation of other pathways that allow cancer cells to escape. Those mechanisms are less clear, however,&rdquo; O&rsquo;Connell said.

ARCHER 1050 is an open-label trial that will divide an estimated 440 patients at sites in Asia and Europe between two arms (

). The first group will take dacomitinib 45 mg orally once daily, while the other group will take gefitinib 250 mg orally once daily. The study, which began in April, should be completed by December 2016. The primary outcome measure is progression-free survival (PFS). Overall survival (OS), including at 30 months, is a secondary measure.

The study was initiated on the basis of data obtained in a single-arm phase II trial (A7471017) of dacomitinib as first-line treatment for advanced NSCLC, including a cohort of patients with EGFR-activating mutations and another with

gene mutations or amplifications. Mok, who was a principal investigator for the earlier trial with Pasi J&auml;nne, MD, PhD, director of the Lowe Center for Thoracic Oncology at the Dana-Farber Cancer Institute in Boston, described the rates of PFS observed in that study as &ldquo;relatively prolonged compared to historic data.&rdquo;

TABLE 1. ARCHER 1050: A Randomized, Open Label Phase 3 Efficacy and Safety Study Of Dacomitinib (PF-00299804) Vs. Gefitinib for the First-Line Treatment of Locally Advanced or Metastatic NSCLC in Subjects With EGFR Activating Mutations

assessment; best overall response; duration

of response; overall safety profile; patient-reported

of life; patient-reported outcomes by EQ-5D

Evidence of pathologically confirmed, advanced NSCLC (with known histology) with the presence of EGFR activating mutation (exon 19 deletion or the

Acceptable for subjects with the presence of the exon 20 T790M

mutation together with either EGFR activating mutation (exon 19 deletion

or the L858R mutation in exon 21) to be included

No prior treatment with systemic therapy for NSCLC

Adequate renal, hematologic, liver function

No evidence of mixed histology that includes elements of small cell or

Any other mutation other than exon 19 deletion or

in exon 21, with or without the presence of the exon 20

Any history of brain metastases or leptomeningeal metastases

Dacomitinib (PF-00299804) 45-mg tablets, continuous oral daily dosing

Gefitinib 250-mg tablets, continuous oral daily dosing

Principal adverse events observed in the phase II study of dacomitinib (A7471017) were diarrhea and skin and nail changes

ECOG PS = Eastern Cooperative Oncology Group performance status; NSCLC = nonsmall cell lung cancer; OS = overall survival; PFS = progression-free survival.

Of the 53 participants identified with EGFR-activating mutations, the majority of whom were never-smokers, 74% remained progression-free at 1 year. Nearly all (96%) of a subset of patients with mutations in

exons 19 and 21 were progression-free at 4 months, the primary endpoint of the study, and the preliminary median PFS for that group of 46 patients was 17 months.

The results, presented at the American Society of Clinical Oncology 2012 Annual Meeting, were from the EGFR cohort of the study. The HER2 cohort was recruiting patients at the time, and data were not yet available.

&ldquo;To me, this is a very important study, as this may take us to the next stage of offering a &lsquo;better&rsquo; TKI for our patients,&rdquo; Mok added. &ldquo;The new drug is promising for higher efficacy. However, we must note the potential toxicity, including skin rash, diarrhea, and mucositis. In my experience, it is essential to treat the toxicity early on; thus we have installed clear protocols for toxicity management.&rdquo;

In the phase II study, there were 21 grade 3 adverse events and two grade 4 adverse events, but no treatmentrelated deaths. The most common side effects included diarrhea and skin and nail changes. Three out of 46 patients in the cohort of participants with

exon 19 or 21 mutations discontinued dacomitinib due to treatmentrelated side effects.

A related phase II trial now under way, ARCHER 1042, is evaluating the effect of prophylactic intervention and an interrupted dosing schedule on the incidence of adverse events in patients treated with dacomitinib. That study, which began in December 2011, should be completed by August 2014.

Dacomitinib was designed as an irreversible inhibitor of the ATP binding site; the molecular bond it forms permanently blocks the binding site, inactivating HER receptor molecules by turning off the intracellular component of those cells that transmits the signaling that leads to growth, proliferation, and metastasis, O&rsquo;Connell said.

&ldquo;TKI inhibitors compete with ATP to enter the binding site and block it, like two people trying to go through the same doorway, whereas dacomitinib forms a covalent bond within the signaling pocket that prevents ATP from triggering further activity, like locking the doorway,&rdquo; he said. First-generation TKIs such as gefitinib and erlotinib are reversible inhibitors.

Dacomitinib was also designed to block three of the four HER receptorsHER1 (EGFR), HER2 and HER4&mdash; which interact with each other in a variety of cancers, whereas first-generation EGFR inhibitors target only one receptor, O&rsquo;Connell said.

Mok noted, for example, that HER2 is a partnering pathway with EGFR, forming chemical bonds (dimers) that activate the downstream pathway. The altered activity of a specific HER receptor can also be functionally compensated for by another HER receptor or other signaling pathways. The crosstalk can result in compensatory tumor signaling and growth, which can lead to drug resistance.

Dacomitinib functions as a pan-HER inhibitor because there are enough similarities in the three HER binding sites it targets to enable it to bind with all three. By contrast, the HER3 receptor is &ldquo;an important partner,&rdquo; O&rsquo;Connell said, but cannot be blocked by TKI small molecules because it lacks the ATP binding site.

&ldquo;Irreversible inhibitors have not been a major focus of research and development to date, in part over concerns that they exacerbate toxicity, and so there are very few. This was really a theoretical concernbut what&rsquo;s been found in practice is that the drugs are tolerable and comparable to other oral drugs and chemotherapy in terms of tolerability,&rdquo; O&rsquo;Connell said. &ldquo;But they are part of a new push. With a better understanding about the molecular biology&mdash;elements like the ATP binding pocket and how it works in cell signaling&mdash;and why resistance develops, there has been a realization that stronger blockade of the signaling may be more effective.&rdquo;

In a related phase III trial, ARCHER 1009, dacomitinib is compared with erlotinib, without a focus on patients with specific mutations (the study is no longer recruiting participants). The primary endpoint in that trial is also PFS. In an earlier phase II trial of dacomitinib versus erlotinib, 188 patients who had received one or two prior chemotherapy regimens were divided between a dacomitinib arm and an erlotinib arm. Median PFS was 2.86 months for patients treated with dacomitinib and 1.91 months for patients treated with erlotinib, and median OS was 9.53 months for patients treated with dacomitinib and 7.44 months for patients treated with erlotinib. Common treatment-related adverse events were dermatologic and gastrointestinal, predominantly grade 1 to 2, and more frequent with dacomitinib.

O&rsquo;Connell said that Pfizer is also looking at the role of dacomitinib in targeting the HER signaling pathway in gastrointestinal cancer, head and neck cancer, and glioblastoma. There are also ongoing preclinical studies of the drug in bladder and pancreatic cancers.

Carpenter RL, Lo H-W. Dacomitinib, an emerging HER-targeted therapy for non-small cell lung cancer.

Huang Z, Brdlik C, Jin P, Shepard HM. A pan-HER approach for cancer therapy: background, current status and future development.

Ramalingam SS, Blackhall F, Krzakowski M, et al. Randomized phase II study of dacomitinib (PF-00299804), an irreversible panhuman epidermal growth factor receptor inhibitor, versus erlotinib in patients with advanced non-small-cell lung cancer.

The second-generation TKI dacomitinib, designed to treat NSCLC, is being evaluated in a clinical trial that will measure the drugâ€™s effectiveness as a first-line treatment.

Tracey Regan | Authors

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CheckMate 067: Phase III Study of Nivolumab in Melanoma

ARCHER-1050: A Study of Dacomitinib vs Gefitinib in First-Line Treatment of Advanced NSCLC